PROJECTSUMMARY The opioid-epidemic, rooted in a chronic-relapsing disease, has had devastating consequences leading to profound national burden. Research into the enhancement of treatment options for individuals with opioid use disorder(OUD)isclearlyapriority.Respondingtourgentcallsfornon-opioidtreatment,wehavebeenevaluating the therapeutic potential of cannabidiol (CBD), a non-intoxicating cannabinoid. Our preclinical animal studies haveshownthatCBDdecreasescue-inducedheroinseekingbehaviorduringdrugabstinence,associatedwith incubationofcraving.WehavealsoshownthatCBDwassafeevenincombinationwithapotentopioidagonist to address a potential relapse condition and that CBD decreased craving and anxiety associated with heroin cues in abstinent individuals with heroin use disorder, an effect that persisted even a week after the last CBD dose. Building on this foundation and recognizing that cannabinoids such as CBD have, to date, poor bioavailability,weproposetoinvestigateanoralCBDpoweredbyanovelpatentedtechnology(leveragingthe kineticsoflongchainfattyacidabsorption)inagelcapdeliverysystemthatimprovesbioavailability,reducesthe incidence of gastrointestinal side effects, reduces first pass metabolism and enhances onset time. In a randomized,double-blinded,placebo-controlledstudyofMED-CBD,weaimtodeterminethepharmacokinetic andpharmacodynamiceffectsinOUDparticipantsandobtaininsightsabouttheconcentrationrangeofMED- CBDthatacutelyreducecravinginOUDindividuals(UG3phase).LeveragingourlargeOUDpopulation(~6,500) at the Addiction Institute of Mount Sinai and usingecological momentary assessment technology to monitor cravinginreal-time,wewillstudyvariousdosesMED-CBDeffectsonopioidabstinentindividualsnotmaintained onmedicationassistedtherapyaswellasonthosemanagedonopioidagonists.Subsequently,alargeclinical trial based on the UG3 results will investigate the long-term (6 months) and the potential protracted effects (6 weeks) of MED-CBD administration on general and cue-induced craving, relapse, opioid medication dose as wellaspsychosocialfunctioninginOUDopiate-abstinentparticipantsmanagedonopioidagonists(UH3phase). These studies will provide concrete information necessary to develop a non-opioid, non-intoxicating FDA- approvedmedicationtoreducecraving,relapseandrestoreglobalfunctioninginOUDindividuals.